Nathalie Turle-Lorenzo

Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to l-DOPA (l-3,4-dihydroxyphenylalanine) for the treatment of Parkinsons disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/μl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after l-AP4 (1 nmol) or picrotoxin, a GABAA receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. l-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.

The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease

Parkinsons disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.

Functional interaction between adenosine A2a and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats

Non-dopaminergic drugs acting either on adenosine A2A or metabotropic glutamate (mGlu) receptors reduce motor impairment in animal models of Parkinsons disease (PD), suggesting a possible functional interaction between these receptors to regulate basal ganglia function. The present study therefore tested the behavioural effects of compounds acting selectively on A2A or on specific mGlu receptor subtypes, alone or in combination, in rodent models of PD. Acute administration of the adenosine A2A receptor antagonists CSC or MSX-3 at the highest doses tested (5 and 1.25mg/kg, respectively) significantly reduces haloperidol-induced catalepsy. Furthermore, the anticataleptic effect of MSX-3 was enhanced by a 3-week treatment. Acute administration of the selective group III mGlu agonist ACPT-I produces potent anticataleptic effects and prolongs time on rotarod of 6-OHDA-lesioned rats. In contrast, acute or chronic administration of MPEP (mGlu5 receptor antagonist) has no anticataleptic action. Furthermore, the acute co-administration of ACPT-I 1mg/kg, but not 5mg/kg, with CSC markedly reduces catalepsy. Opposite effects are observed after a 3-week co-administration. The co-administration of ACPT-I with MSX-3 has anticataleptic effects both after acute or chronic treatment. In contrast, acute combination of subthreshold doses of CSC and MPEP has no effect. After a 3-week treatment, however, the combination of CSC and MPEP was found to reduce haloperidol-induced catalepsy. Altogether, these results show for the first time that systemic activation of group III mGlu receptors with ACPT-I provides benefits in parkinsonian rats and underlie a possible interaction with A2A receptors to regulate basal ganglia motor function.

The Dopamine Agonist Piribedil with L-DOPA Improves Attentional Dysfunction: Relevance for Parkinson's Disease

Cognitive deficits are often associated with motor symptoms in Parkinsons disease. This study investigates the ability of piribedil ([(methylenedioxy-3,4 benzyl)-4 pyperazinyl-1]-2 pyrimidine), a D2/D3 dopamine (DA) receptor agonist with antagonist activity at α2A-adrenoceptors, to restore motor and attentional deficits in nigrostriatal 6-hydroxydopamine-lesioned rats. Subjects were trained to depress a lever, detect a stimulus occurring after variable foreperiods, and release the lever quickly afterward. Striatal DA depletions produce deficits in the timing of foreperiods and prolong reaction times. Although a subchronic treatment with piribedil (0.1–2 mg/kg) is not effective, a dose of 0.3 mg/kg administered for 3 weeks significantly reverses the akinetic deficits produced by the striatal dopamine depletion and progressively improves attentional deficits. When coadministered with the dopamine prodrug l-3,4-dihydroxyphenylalanine (l-DOPA) (3 mg/kg), piribedil (0.3 mg/kg) promotes a rapid and full recovery of preoperative performance. These results suggest that administration of l-DOPA in combination with piribedil in a chronic treatment as either initial or supplemental therapy for Parkinsons disease might improve cognitive functions while reducing the risk for motor complications.

Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences

&NA; Parkinsons disease (PD) is a progressive neurodegenerative disease originating from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). The small‐conductance calcium‐activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task. We used a rat model of early PD in which the progressive nigrostriatal DA degeneration was produced by bilateral infusions of 6‐hydroxydopamine (6‐OHDA) into the striatum. In situ hybridization of SK2 and SK3 mRNA and binding of iodinated apamin (SK2/SK3 blocker) were performed at 1, 8 or 21 days postsurgery in sham and 6‐OHDA lesion groups. A significant decrease of SK3 channel expression was found in the SNC of lesioned animals at the three time points, with no change of SK2 channel expression. Interestingly, an upregulation of SK2 mRNA and apamin binding was found in the subthalamic nucleus (STN) at 21 days postlesion. These results were confirmed using quantitative real time polymerase chain reaction (qRT‐PCR) approach. Functionally, the local infusion of apamin into the STN of parkinsonian rats enhanced the akinetic deficits produced by nigrostriatal DA lesions in a reaction time task while apamin infusion into the SNC had an opposite effect. These effects disappear when the positive modulator of SK channels (CyPPA) is co‐administered with apamin. These findings suggest that an upregulation of SK2 channels in the STN may underlie the physiological adjustment to increased subthalamic excitability following partial DA denervation. Highlights In a rat model of Parkinsonism:Upregulation of SK2 channel expression in the subthalamic nucleus.Decrease of SK3 channel expression level in the substantia nigra pars compacta.Behavioral performance in a reaction time task of 6‐OHDA‐lesioned rat.Impairment by SK channel blockade with apamin in the subthalamic nucleus.Improvement by SK channel blockade with apamin in the substantia nigra pars compacta.

Dynamics of Executive Control and Motor Deficits in Parkinsonian Rats

While there is general agreement that in Parkinsons disease (PD), striatal dopamine (DA) depletion causes motor deficits, the origin of the associated cognitive impairments remains a matter of debate. The present study aimed to decipher the influence of a partial 6-hydroxydopamine (6-OHDA) lesion of striatal DA nerve terminals in rats performing a reaction time task previously used to assess cognitive deficits in PD patients. The effects of two behavioral manipulations—foreperiod duration and stimulus–response congruence—known to affect motor processes and executive control, respectively, were studied over 8 weeks postsurgery in control and lesion animals. Two weeks after surgery, the lesion abolished the effect of foreperiod, confirming the direct involvement of striatal DA in motor processes, but failed to alter the effect of congruence. During the following weeks, the effect of foreperiod was reinstated, indicating a recovery of lesion-induced motor symptoms. This recovery was accompanied by a progressive increase of the congruence effect, signaling an executive control deficit in lesion animals. This result provides the first evidence that 6-OHDA lesioned rats exhibit the same cognitive impairment as PD patients in this task. The deficit, however, built up progressively after the lesion and may result from adaptations mitigating lesion-induced motor deficits.